Microbiota-Mitochondria Inter-Talk: A Potential Therapeutic Strategy in Obesity and Type 2 Diabetes

Abstract

The rising prevalence of obesity and type 2 diabetes (T2D) is a growing concern worldwide. New discoveries in the field of metagenomics and clinical research have revealed that the gut microbiota plays a key role in these metabolic disorders. The mechanisms regulating microbiota composition are multifactorial and include resistance to stress, presence of pathogens, diet, cultural habits and general health conditions. Recent evidence has shed light on the influence of microbiota quality and diversity on mitochondrial functions. Of note, the gut microbiota has been shown to regulate crucial transcription factors, coactivators, as well as enzymes implicated in mitochondrial biogenesis and metabolism. Moreover, microbiota metabolites seem to interfere with mitochondrial oxidative/nitrosative stress and autophagosome formation, thus regulating the activation of the inflammasome and the production of inflammatory cytokines, key players in chronic metabolic disorders. This review focuses on the association between intestinal microbiota and mitochondrial function and examines the mechanisms that may be the key to their use as potential therapeutic strategies in obesity and T2D management.

Keywords: gut microbiota; inflammation; mitochondria; mitochondrial oxidative/nitrosative stress; obesity; type 2 diabetes.

Figure 1

General mechanisms of ROS-induced mitochondrial dysfunction in obese and type 2 diabetes (T2D) patients. Dysregulated/impaired systemic inflammation, glucotoxicity and lipotoxicity triggers mtROS and RNS generation by mitochondrial ETC. Nitrosative stress also inhibits mitochondrial complexes and O₂ consumption, as it is more reactive to ROS. As a result, the cytokines pro-IL-1β and pro-IL-18 and the inflammasome complex are activated through NF-кB translocation in the nucleus. Moreover, mtROS stimulates an increase in antioxidant defense signaling in order to modulate oxidative stress homeostasis. Disrupted mitochondria are targeted by autophagosomes in a process called mitophagy, which aims to restore the mitochondrial function. Abbreviations: ETC, electron transport chain; IL-1β, interleukin-1β; IL-18, interleukin-18; KEAP1, Kelch-like ECH-associated protein 1; mtROS, mitochondrial ROS; NF-кB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor erythroid 2-related factor 2; RNS, reactive nitrogen species; NO, nitric oxide; ONOO-, peroxynitrite; NLRP3, NLRP3 (nucleotide oligomerization domain (NOD), leucine-rich repeat (LRR) and pyrin domain (PYD)) and ROS, reactive oxygen species.

Figure 2

Role of gut microbiota in the development of obesity and T2D, including some of the mechanisms thought to contribute to alterations of the host metabolic state. Up and down arrows indicate an increase and decrease, respectively. Abbreviations: IEC, intestinal epithelial cells; LPS, lipopolysaccharide; LDL-C, low-density lipoproteins-cholesterol; SCFAs, short-chain fatty acids; CVD, cardiovascular disease and TJ, tight junction.

Figure 3

Microbiota-mitochondria inter-talk: Increased gut permeability in obese and T2D patients can induce LPS translocation to the bloodstream, along with a further inflammatory cascade, ROS and H₂S production, as well as inflammasome NLRP3 activation, thus resulting in a mitochondria-mediated inflammatory response. The inhibition of AMPK activation and decreased expression of UCP-2 lead to a reduced glucose metabolism and to the partial uncoupling of mitochondrial oxidative phosphorylation, as well as an increased ROS production. Moreover, microbiota-released metabolites can also undermine or promote mitochondrial biogenesis and energy metabolism. Concurrently, mitochondrial ROS production can regulate gut microbiota activity and composition by modulating mucosal immune responses and intestinal barrier functions. Abbreviations: AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; COX, cyclooxygenase; H₂S, hydrogen sulphide; IEC, intestinal epithelial cells; LPS, lipopolysaccharide; NLRP3, inflammasome NOD-like receptor family and pyrin domain containing 3; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitrogen oxide; ROS, reactive oxygen species; SCFAs, short-chain fatty acids and UCP-2, uncoupling protein 2.